PET imaging of neuroinflammation: any credible alternatives to TSPO yet?

Jones HB. Some instances of the contrast between delirium tremens and inflammation of the brain, as regards the quantity of phosphoric acid excreted by the kidneys. Med Chir Trans. 1847;30:21–38.

pubmed: 20895873 pmcid: 2104022 doi: 10.1177/095952874703000105

Gomez-Nicola D, Perry VH. Microglial dynamics and role in the healthy and diseased brain: a paradigm of functional plasticity. Neuroscientist. 2015;21:169–84.

pubmed: 24722525 pmcid: 4412879 doi: 10.1177/1073858414530512

Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration. Nat Rev Neurosci. 2001;2:734–44.

pubmed: 11584311 doi: 10.1038/35094583

Benavides J, Quarteronet D, Imbault F, Malgouris C, Uzan A, Renault C, et al. Labelling of “peripheral-type” benzodiazepine binding sites in the rat brain by using [3H]PK 11195, an isoquinoline carboxamide derivative: kinetic studies and autoradiographic localization. J Neurochem. 1983;41:1744–50.

pubmed: 6315880 doi: 10.1111/j.1471-4159.1983.tb00888.x

Le Fur G, Vaucher N, Perrier ML, Flamier A, Benavides J, Renault C, et al. Differentiation between two ligands for peripheral benzodiazepine binding sites, [3H]RO5-4864 and [3H]PK 11195, by thermodynamic studies. Life Sci. 1983;33:449–57.

pubmed: 6308375 doi: 10.1016/0024-3205(83)90794-4

Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapere JJ, Lindemann P, et al. Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci. 2006;27:402–9.

pubmed: 16822554 doi: 10.1016/j.tips.2006.06.005

Banati RB. Visualising microglial activation in vivo. Glia. 2002;40:206–17.

pubmed: 12379908 doi: 10.1002/glia.10144

Owen DR, Matthews PM. Imaging brain microglial activation using positron emission tomography and translocator protein-specific radioligands. Int Rev Neurobiol. 2011;101:19–39.

pubmed: 22050847 doi: 10.1016/B978-0-12-387718-5.00002-X

Chauveau F, Boutin H, Van Camp N, Dolle F, Tavitian B. Nuclear imaging of neuroinflammation: a comprehensive review of [11C]PK11195 challengers. Eur J Nucl Med Mol Imaging. 2008;35:2304–19.

pubmed: 18828015 doi: 10.1007/s00259-008-0908-9

Wimberley C, Buvat I, Boutin H. Imaging translocator protein expression with positron emission tomography. Eur J Nucl Med Mol Imaging. 2021;49:74–76.

pubmed: 34729627 doi: 10.1007/s00259-021-05601-y

Chauveau F, Becker G, Boutin H. Have (R)-[(11)C]PK11195 challengers fulfilled the promise? A scoping review of clinical TSPO PET studies. Eur J Nucl Med Mol Imaging. 2021;49:201–20.

pubmed: 34387719 pmcid: 8712292 doi: 10.1007/s00259-021-05425-w

Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, et al. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab. 2012;32:1–5.

pubmed: 22008728 doi: 10.1038/jcbfm.2011.147

Owen DR, Gunn RN, Rabiner EA, Bennacef I, Fujita M, Kreisl WC, et al. Mixed-affinity binding in humans with 18-kDa translocator protein ligands. J Nucl Med. 2011;52:24–32.

pubmed: 21149489 doi: 10.2967/jnumed.110.079459

Tiwari AK, Ji B, Yui J, Fujinaga M, Yamasaki T, Xie L, et al. 18F]FEBMP: positron emission tomography imaging of TSPO in a model of neuroinflammation in rats, and in vitro autoradiograms of the human brain. Theranostics. 2015;5:961–9.

pubmed: 26155312 pmcid: 4493534 doi: 10.7150/thno.12027

MacAskill MG, Stadulyte A, Williams L, Morgan TEF, Sloan NL, Alcaide-Corral CJ, et al. Quantification of macrophage-driven inflammation during myocardial infarction with (18)F-LW223, a novel TSPO radiotracer with binding independent of the rs6971 human polymorphism. J Nucl Med. 2021;62:536–44.

pubmed: 32859708 pmcid: 8049364 doi: 10.2967/jnumed.120.243600

Gui Y, Marks JD, Das S, Hyman BT, Serrano-Pozo A. Characterization of the 18 kDa translocator protein (TSPO) expression in post-mortem normal and Alzheimer’s disease brains. Brain Pathol. 2020;30:151–64.

pubmed: 31276244 doi: 10.1111/bpa.12763

Rizzo G, Veronese M, Tonietto M, Bodini B, Stankoff B, Wimberley C, et al. Generalization of endothelial modelling of TSPO PET imaging: Considerations on tracer affinities. J Cereb Blood Flow Metab. 2019;39:874–85.

pubmed: 29135382 doi: 10.1177/0271678X17742004

Wimberley C, Lavisse S, Brulon V, Peyronneau MA, Leroy C, Bodini B, et al. Impact of endothelial 18-kDa translocator protein on the quantification of (18)F-DPA-714. J Nucl Med. 2018;59:307–14.

pubmed: 28775204 doi: 10.2967/jnumed.117.195396

Veronese M, Reis Marques T, Bloomfield PS, Rizzo G, Singh N, Jones D, et al. Kinetic modelling of [(11)C]PBR28 for 18 kDa translocator protein PET data: a validation study of vascular modelling in the brain using XBD173 and tissue analysis. J Cereb Blood Flow Metab. 2018;38:1227–42.

pubmed: 28580888 doi: 10.1177/0271678X17712388

Setiawan E, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Rajkowska G, et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry. 2015;72:268–75.

pubmed: 25629589 pmcid: 4836849 doi: 10.1001/jamapsychiatry.2014.2427

Su L, Faluyi YO, Hong YT, Fryer TD, Mak E, Gabel S, et al. Neuroinflammatory and morphological changes in late-life depression: the NIMROD study. Br J Psychiatry. 2016;209:525–6.

pubmed: 27758838 pmcid: 5152879 doi: 10.1192/bjp.bp.116.190165

Holmes SE, Hinz R, Conen S, Gregory CJ, Matthews JC, Anton-Rodriguez JM, et al. Elevated translocator protein in anterior cingulate in major depression and a role for inflammation in suicidal thinking: a positron emission tomography study. Biol Psychiatry. 2018;83:61–69.

pubmed: 28939116 doi: 10.1016/j.biopsych.2017.08.005

Meyer JH, Cervenka S, Kim MJ, Kreisl WC, Henter ID, Innis RB. Neuroinflammation in psychiatric disorders: PET imaging and promising new targets. Lancet Psychiatry. 2020;7:1064–74.

pubmed: 33098761 pmcid: 7893630 doi: 10.1016/S2215-0366(20)30255-8

van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A, Caspers E, et al. Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biol Psychiatry. 2008;64:820–2.

pubmed: 18534557 doi: 10.1016/j.biopsych.2008.04.025

Doorduin J, de Vries EF, Willemsen AT, de Groot JC, Dierckx RA, Klein HC. Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med. 2009;50:1801–7.

pubmed: 19837763 doi: 10.2967/jnumed.109.066647

Bloomfield PS, Selvaraj S, Veronese M, Rizzo G, Bertoldo A, Owen DR, et al. Microglial activity in people at ultra high risk of psychosis and in schizophrenia: an [(11)C]PBR28 PET brain imaging study. Am J Psychiatry. 2016;173:44–52.

pubmed: 26472628 doi: 10.1176/appi.ajp.2015.14101358

Takano A, Arakawa R, Ito H, Tateno A, Takahashi H, Matsumoto R, et al. Peripheral benzodiazepine receptors in patients with chronic schizophrenia: a PET study with [11C]DAA1106. The international journal of neuropsychopharmacology. 2010;13:943–50.

pubmed: 20350336 doi: 10.1017/S1461145710000313

Kenk M, Selvanathan T, Rao N, Suridjan I, Rusjan P, Remington G, et al. Imaging neuroinflammation in gray and white matter in schizophrenia: an in-vivo PET study with [18F]-FEPPA. Schizophr Bull. 2015;41:85–93.

pubmed: 25385788 doi: 10.1093/schbul/sbu157

Holmes SE, Hinz R, Drake RJ, Gregory CJ, Conen S, Matthews JC, et al. In vivo imaging of brain microglial activity in antipsychotic-free and medicated schizophrenia: a [(11)C](R)-PK11195 positron emission tomography study. Mol Psychiatry. 2016;21:1672–9.

pubmed: 27698434 doi: 10.1038/mp.2016.180

van der Doef TF, de Witte LD, Sutterland AL, Jobse E, Yaqub M, Boellaard R, et al. In vivo (R)-[(11)C]PK11195 PET imaging of 18kDa translocator protein in recent onset psychosis. NPJ Schizophr. 2016;2:16031.

pubmed: 27602389 pmcid: 5007116 doi: 10.1038/npjschz.2016.31

Di Biase MA, Zalesky A, O’Keefe G, Laskaris L, Baune BT, Weickert CS, et al. PET imaging of putative microglial activation in individuals at ultra-high risk for psychosis, recently diagnosed and chronically ill with schizophrenia. Transl Psychiatry. 2017;7:e1225.

pubmed: 28850113 pmcid: 5611755 doi: 10.1038/tp.2017.193

Hafizi S, Tseng HH, Rao N, Selvanathan T, Kenk M, Bazinet RP, et al. Imaging microglial activation in untreated first-episode psychosis: a PET study with [(18)F]FEPPA. Am J Psychiatry. 2017;174:118–24.

pubmed: 27609240 doi: 10.1176/appi.ajp.2016.16020171

Conen S, Gregory CJ, Hinz R, Smallman R, Corsi-Zuelli F, Deakin B, et al. Neuroinflammation as measured by positron emission tomography in patients with recent onset and established schizophrenia: implications for immune pathogenesis. Mol Psychiatry. 2021;26:5398–406.

pubmed: 32606376 doi: 10.1038/s41380-020-0829-y

Collste K, Plaven-Sigray P, Fatouros-Bergman H, Victorsson P, Schain M, Forsberg A, et al. Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [(11)C]PBR28. Mol Psychiatry. 2017;22:850–6.

pubmed: 28194003 doi: 10.1038/mp.2016.247

De Picker LJ, Haarman BCM. Applicability, potential and limitations of TSPO PET imaging as a clinical immunopsychiatry biomarker. Eur J Nucl Med Mol Imaging. 2021;49:164–73.

pubmed: 33735406 doi: 10.1007/s00259-021-05308-0

Iliopoulou SM, Tsartsalis S, Kaiser S, Millet P, Tournier BB. Dopamine and neuroinflammation in schizophrenia - interpreting the findings from translocator protein (18kDa) PET imaging. Neuropsychiatr Dis Treat. 2021;17:3345–57.

pubmed: 34819729 pmcid: 8608287 doi: 10.2147/NDT.S334027

Coughlin JM, Wang Y, Ambinder EB, Ward RE, Minn I, Vranesic M, et al. In vivo markers of inflammatory response in recent-onset schizophrenia: a combined study using [(11)C]DPA-713 PET and analysis of CSF and plasma. Transl Psychiatry. 2016;6:e777.

pubmed: 27070405 pmcid: 4872398 doi: 10.1038/tp.2016.40

Narayanaswami V, Dahl K, Bernard-Gauthier V, Josephson L, Cumming P, Vasdev N. Emerging PET radiotracers and targets for imaging of neuroinflammation in neurodegenerative diseases: outlook beyond TSPO. Mol Imaging. 2018;17:1536012118792317.

pubmed: 30203712 pmcid: 6134492 doi: 10.1177/1536012118792317

Janssen B, Vugts DJ, Windhorst AD, Mach RH. PET imaging of microglial activation-beyond targeting TSPO. Molecules 2018; 23: https://doi.org/10.3390/molecules23030607 .

Suzuki Y, Nakamura Y, Yamada K, Kurabe S, Okamoto K, Aoki H, et al. Aquaporin positron emission tomography differentiates between grade III and IV human astrocytoma. Neurosurgery. 2018;82:842–6.

pubmed: 28645205 doi: 10.1093/neuros/nyx314

Chen Z, Yang A, Zhang J, Chen A, Zhang Y, Huang C, et al. CXCR4-Directed PET/CT with [(68)Ga]pentixafor in central nervous system lymphoma: a comparison with [(18)F]FDG PET/CT. Mol Imaging Biol. 2022;24:416–24.

pubmed: 34651291 doi: 10.1007/s11307-021-01664-3

Starzer AM, Berghoff AS, Traub-Weidinger T, Haug AR, Widhalm G, Hacker M, et al. Assessment of central nervous system lymphoma based on CXCR4 expression in vivo using 68Ga-pentixafor PET/MRI. Clin Nucl Med. 2021;46:16–20.

pubmed: 33208624 pmcid: 8385649 doi: 10.1097/RLU.0000000000003404

van der Wildt B, Wilhelmus MM, Bijkerk J, Haveman LY, Kooijman EJ, Schuit RC, et al. Development of carbon-11 labeled acryl amides for selective PET imaging of active tissue transglutaminase. Nucl Med Biol. 2016;43:232–42.

pubmed: 27067043 doi: 10.1016/j.nucmedbio.2016.01.003

Ackermann U, Jager L, Rigopoulos A, Burvenich IJG, O’Keefe GJ, Scott AM. (18)F-labeling and initial in vivo evaluation of a Hitomi peptide for imaging tissue transglutaminase 2. Nucl Med Biol. 2023;116-117:108308.

Meyer PT, Elmenhorst D, Matusch A, Winz O, Zilles K, Bauer A. A1 adenosine receptor PET using [18F]CPFPX: displacement studies in humans. Neuroimage. 2006;32:1100–5.

pubmed: 16806981 doi: 10.1016/j.neuroimage.2006.04.202

Barret O, Hannestad J, Vala C, Alagille D, Tavares A, Laruelle M, et al. Characterization in humans of 18F-MNI-444, a PET radiotracer for brain adenosine 2A receptors. J Nucl Med. 2015;56:586–91.

pubmed: 25698783 doi: 10.2967/jnumed.114.152546

Joya A, Ardaya M, Montilla A, Garbizu M, Plaza-Garcia S, Gomez-Vallejo V, et al. In vivo multimodal imaging of adenosine A(1) receptors in neuroinflammation after experimental stroke. Theranostics. 2021;11:410–25.

pubmed: 33391483 pmcid: 7681082 doi: 10.7150/thno.51046

Rissanen E, Virta JR, Paavilainen T, Tuisku J, Helin S, Luoto P, et al. Adenosine A2A receptors in secondary progressive multiple sclerosis: a [(11)C]TMSX brain PET study. J Cereb Blood Flow Metab. 2013;33:1394–401.

pubmed: 23695433 pmcid: 3764386 doi: 10.1038/jcbfm.2013.85

Karasawa A, Kawate T. Structural basis for subtype-specific inhibition of the P2X7 receptor. Elife 2016;5:e22153.

McCarthy AE, Yoshioka C, Mansoor SE. Full-length P2X(7) structures reveal how palmitoylation prevents channel desensitization. Cell. 2019;179:659–670 e613.

pubmed: 31587896 pmcid: 7053488 doi: 10.1016/j.cell.2019.09.017

Burnstock G, Boeynaems JM. Purinergic signalling and immune cells. Purinergic Signal. 2014;10:529–64.

pubmed: 25352330 pmcid: 4272370 doi: 10.1007/s11302-014-9427-2

Di Virgilio F, Dal Ben D, Sarti AC, Giuliani AL, Falzoni S. The P2X7 receptor in infection and inflammation. Immunity. 2017;47:15–31.

pubmed: 28723547 doi: 10.1016/j.immuni.2017.06.020

Beltran-Lobo P, Reid MJ, Jimenez-Sanchez M, Verkhratsky A, Perez-Nievas BG, Noble W. Astrocyte adaptation in Alzheimer’s disease: a focus on astrocytic P2X7R. Essays Biochem. 2023;67:119–30.

pubmed: 36449279 pmcid: 10011405 doi: 10.1042/EBC20220079

Illes P, Verkhratsky A, Burnstock G, Franke H. P2X receptors and their roles in astroglia in the central and peripheral nervous system. Neuroscientist. 2012;18:422–38.

pubmed: 22013151 doi: 10.1177/1073858411418524

Bhattacharya A, Biber K. The microglial ATP-gated ion channel P2X7 as a CNS drug target. Glia. 2016;64:1772–87.

pubmed: 27219534 doi: 10.1002/glia.23001

Illes P, Khan TM, Rubini P. Neuronal P2X7 receptors revisited: do they really exist? J Neurosci. 2017;37:7049–62.

pubmed: 28747388 pmcid: 6705732 doi: 10.1523/JNEUROSCI.3103-16.2017

Adinolfi E, Capece M, Amoroso F, De Marchi E, Franceschini A. Emerging roles of P2X receptors in cancer. Curr Med Chem. 2015;22:878–90.

pubmed: 25312206 doi: 10.2174/0929867321666141012172913

Burnstock G. Purinergic signalling and disorders of the central nervous system. Nat Rev Drug Discov. 2008;7:575–90.

pubmed: 18591979 doi: 10.1038/nrd2605

Monif M, Burnstock G, Williams DA. Microglia: proliferation and activation driven by the P2X7 receptor. Int J Biochem Cell Biol. 2010;42:1753–6.

pubmed: 20599520 doi: 10.1016/j.biocel.2010.06.021

Oliveira-Giacomelli A, Petiz LL, Andrejew R, Turrini N, Silva JB, Sack U, et al. Role of P2X7 receptors in immune responses during neurodegeneration. Front Cell Neurosci. 2021;15:662935.

pubmed: 34122013 pmcid: 8187565 doi: 10.3389/fncel.2021.662935

Territo PR, Zarrinmayeh H. P2X(7) receptors in neurodegeneration: potential therapeutic applications from basic to clinical approaches. Front Cell Neurosci. 2021;15:617036.

pubmed: 33889073 pmcid: 8055960 doi: 10.3389/fncel.2021.617036

von Mucke-Heim IA, Deussing JM. The P2X7 receptor in mood disorders: emerging target in immunopsychiatry, from bench to bedside. Neuropharmacology. 2023;224:109366.

doi: 10.1016/j.neuropharm.2022.109366

Janssen B, Vugts DJ, Funke U, Spaans A, Schuit RC, Kooijman E, et al. Synthesis and initial preclinical evaluation of the P2X7 receptor antagonist [(1)(1)C]A-740003 as a novel tracer of neuroinflammation. J Labelled Comp Radiopharm. 2014;57:509–16.

pubmed: 24995673 doi: 10.1002/jlcr.3206

Gao M, Wang M, Green MA, Hutchins GD, Zheng QH. Synthesis of [(11)C]GSK1482160 as a new PET agent for targeting P2X(7) receptor. Bioorg Med Chem Lett. 2015;25:1965–70.

pubmed: 25819093 doi: 10.1016/j.bmcl.2015.03.021

Schmidt S, Isaak A, Junker A. Spotlight on P2X7 Receptor PET Imaging: A Bright Target or a Failing Star? Int J Mol Sci. 2023;24:1374.

Territo PR, Meyer JA, Peters JS, Riley AA, McCarthy BP, Gao M, et al. Characterization of (11)C-GSK1482160 for targeting the P2X7 receptor as a biomarker for neuroinflammation. J Nucl Med. 2017;58:458–65.

pubmed: 27765863 doi: 10.2967/jnumed.116.181354

Huang G, Lu X, Qiu Y, Bi L, Ye P, Yang M, et al. Hetero-aryl bromide precursor fluorine-18 radiosynthesis and preclinical evaluation of a novel positron emission tomography (PET) tracer [(18)F]GSK1482160. Bioorg Med Chem. 2022;73:116996.

pubmed: 36126443 doi: 10.1016/j.bmc.2022.116996

Hagens MHJ, Golla SSV, Janssen B, Vugts DJ, Beaino W, Windhorst AD, et al. The P2X7 receptor tracer [(11)C]SMW139 as an in vivo marker of neuroinflammation in multiple sclerosis: a first-in man study. Eur J Nucl Med Mol Imaging. 2020;47:379–89.

pubmed: 31705174 doi: 10.1007/s00259-019-04550-x

Ory D, Celen S, Gijsbers R, Van Den Haute C, Postnov A, Koole M, et al. Preclinical evaluation of a P2X7 receptor-selective radiotracer: PET studies in a rat model with local overexpression of the human P2X7 receptor and in nonhuman primates. J Nucl Med. 2016;57:1436–41.

pubmed: 27199364 doi: 10.2967/jnumed.115.169995

Kolb HC, Barret O, Bhattacharya A, Chen G, Constantinescu C, Huang C, et al. Preclinical evaluation and nonhuman primate receptor occupancy study of (18)F-JNJ-64413739, a PET radioligand for P2X7 receptors. J Nucl Med. 2019;60:1154–9.

pubmed: 30733317 doi: 10.2967/jnumed.118.212696

Van Weehaeghe D, Koole M, Schmidt ME, Deman S, Jacobs AH, Souche E.et al. (11)C]JNJ54173717, a novel P2X7 receptor radioligand as marker for neuroinflammation: human biodistribution, dosimetry, brain kinetic modelling and quantification of brain P2X7 receptors in patients with Parkinson’s disease and healthy volunteers. Eur J Nucl Med Mol Imaging. 2019;46:2051–64.

Koole M, Schmidt ME, Hijzen A, Ravenstijn P, Vandermeulen C, Van Weehaeghe D.et al. (18)F-JNJ-64413739, a novel PET ligand for the P2X7 ion channel: radiation dosimetry, kinetic modeling, test-retest variability, and occupancy of the P2X7 antagonist JNJ-54175446. J Nucl Med. 2019;60:683–90.

Mertens N, Schmidt ME, Hijzen A, Van Weehaeghe D, Ravenstijn P, Depre M, et al. Minimally invasive quantification of cerebral P2X7R occupancy using dynamic [(18)F]JNJ-64413739 PET and MRA-driven image derived input function. Sci Rep. 2021;11:16172.

pubmed: 34373571 pmcid: 8352986 doi: 10.1038/s41598-021-95715-y

Mikkelsen JD, Aripaka SS, Kaad S, Pazarlar BA, Pinborg L, Finsen B, et al. Characterization of the novel P2X7 receptor radioligand [(3)H]JNJ-64413739 in human brain tissue. ACS Chem Neurosci. 2023;14:111–8.

pubmed: 36535632 doi: 10.1021/acschemneuro.2c00561

Notter T, Coughlin JM, Sawa A, Meyer U. Reconceptualization of translocator protein as a biomarker of neuroinflammation in psychiatry. Mol Psychiatry. 2018;23:36–47.

pubmed: 29203847 doi: 10.1038/mp.2017.232

Van Weehaeghe D, Van Schoor E, De Vocht J, Koole M, Attili B, Celen S, et al. TSPO versus P2X7 as a target for neuroinflammation: an in vitro and in vivo study. J Nucl Med. 2020;61:604–7.

pubmed: 31562223 pmcid: 7198372 doi: 10.2967/jnumed.119.231985

Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, et al. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci. 2014;17:131–43.

pubmed: 24316888 doi: 10.1038/nn.3599

Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell. 2017;169:1276–1290 e1217.

pubmed: 28602351 doi: 10.1016/j.cell.2017.05.018

Bennett ML, Bennett FC, Liddelow SA, Ajami B, Zamanian JL, Fernhoff NB, et al. New tools for studying microglia in the mouse and human CNS. Proc Natl Acad Sci USA. 2016;113:E1738–1746.

pubmed: 26884166 pmcid: 4812770 doi: 10.1073/pnas.1525528113

Zhu C, Kros JM, van der Weiden M, Zheng P, Cheng C, Mustafa DA. Expression site of P2RY12 in residential microglial cells in astrocytomas correlates with M1 and M2 marker expression and tumor grade. Acta Neuropathol Commun. 2017;5:4.

pubmed: 28073370 pmcid: 5223388 doi: 10.1186/s40478-016-0405-5

Butovsky O, Weiner HL. Microglial signatures and their role in health and disease. Nat Rev Neurosci. 2018;19:622–35.

pubmed: 30206328 pmcid: 7255106 doi: 10.1038/s41583-018-0057-5

Zrzavy T, Hametner S, Wimmer I, Butovsky O, Weiner HL, Lassmann H. Loss of ‘homeostatic’ microglia and patterns of their activation in active multiple sclerosis. Brain. 2017;140:1900–13.

pubmed: 28541408 pmcid: 6057548 doi: 10.1093/brain/awx113

Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity. 2017;47:566–581 e569.

pubmed: 28930663 pmcid: 5719893 doi: 10.1016/j.immuni.2017.08.008

Beaino W, Janssen B, Kooij G, van der Pol SMA, van Het Hof B, van Horssen J, et al. Purinergic receptors P2Y12R and P2X7R: potential targets for PET imaging of microglia phenotypes in multiple sclerosis. J Neuroinflammation. 2017;14:259.

pubmed: 29273052 pmcid: 5741931 doi: 10.1186/s12974-017-1034-z

Klein B, Mrowetz H, Barker CM, Lange S, Rivera FJ, Aigner L. Age influences microglial activation after cuprizone-induced demyelination. Front Aging Neurosci. 2018;10:278.

pubmed: 30297998 pmcid: 6160739 doi: 10.3389/fnagi.2018.00278

Maeda J, Minamihisamatsu T, Shimojo M, Zhou X, Ono M, Matsuba Y, et al. Distinct microglial response against Alzheimer’s amyloid and tau pathologies characterized by P2Y12 receptor. Brain Commun. 2021;3:fcab011.

pubmed: 33644757 pmcid: 7901060 doi: 10.1093/braincomms/fcab011

Baqi Y, Muller CE. Antithrombotic P2Y(12) receptor antagonists: recent developments in drug discovery. Drug Discov Today. 2019;24:325–33.

pubmed: 30291899 doi: 10.1016/j.drudis.2018.09.021

Janssen AL, Vugts DJ, Funke U, Molenaar GT, Kruijer PS, Dolle F et al. Synthesis of the first carbon-11 labelled P2Y12 receptor antagonist for PET imaging of microglial activation in neuroinflammation. Proc J Labelled Comp Radiopharmaceuticals. 2015;58:S44.

Villa A, Klein B, Janssen B, Pedragosa J, Pepe G, Zinnhardt B, et al. Identification of new molecular targets for PET imaging of the microglial anti-inflammatory activation state. Theranostics. 2018;8:5400–18.

pubmed: 30555554 pmcid: 6276082 doi: 10.7150/thno.25572

Jackson IM, Buccino PJ, Azevedo EC, Carlson ML, Luo ASZ, Deal EM, et al. Radiosynthesis and initial preclinical evaluation of [(11)C]AZD1283 as a potential P2Y12R PET radiotracer. Nucl Med Biol. 2022;114-115:143–50.

pubmed: 35680502 pmcid: 10413622 doi: 10.1016/j.nucmedbio.2022.05.001

van der Wildt B, Janssen B, Pekosak A, Steen EJL, Schuit RC, Kooijman EJM, et al. Novel thienopyrimidine-based PET Tracers for P2Y(12) receptor imaging in the brain. ACS Chem Neurosci. 2021;12:4465–74.

pubmed: 34757711 doi: 10.1021/acschemneuro.1c00641

Xiang C, Li H, Tang W. Targeting CSF-1R represents an effective strategy in modulating inflammatory diseases. Pharmacol Res. 2023;187:106566.

pubmed: 36423789 doi: 10.1016/j.phrs.2022.106566

Chitu V, Biundo F, Stanley ER. Colony stimulating factors in the nervous system. Semin Immunol. 2021;54:101511.

pubmed: 34743926 pmcid: 8671346 doi: 10.1016/j.smim.2021.101511

Bernard-Gauthier V, Schirrmacher R. 5-(4-((4-[(18)F]Fluorobenzyl)oxy)-3-methoxybenzyl)pyrimidine-2,4-diamine: a selective dual inhibitor for potential PET imaging of Trk/CSF-1R. Bioorg Med Chem Lett. 2014;24:4784–90.

pubmed: 25257201 doi: 10.1016/j.bmcl.2014.09.014

Singleton TA, Bdair H, Bailey JJ, Choi S, Aliaga A, Rosa-Neto P, et al. Efficient radiosynthesis and preclinical evaluation of [(18) F]FOMPyD as a positron emission tomography tracer candidate for TrkB/C receptor imaging. J Labelled Comp Radiopharm. 2020;63:144–50.

pubmed: 31919878 doi: 10.1002/jlcr.3827

van der Wildt B, Miao Z, Reyes ST, Park JH, Klockow JL, Zhao N, et al. BLZ945 derivatives for PET imaging of colony stimulating factor-1 receptors in the brain. Nucl Med Biol. 2021;100-101:44–51.

pubmed: 34174546 doi: 10.1016/j.nucmedbio.2021.06.005

Tanzey SS, Shao X, Stauff J, Arteaga J, Sherman P, Scott PJH, et al. Synthesis and initial in vivo evaluation of [(11)C]AZ683-A novel PET radiotracer for colony stimulating factor 1 receptor (CSF1R). Pharmaceuticals (Basel). 2018;11:136.

Horti AG, Naik R, Foss CA, Minn I, Misheneva V, Du Y, et al. PET imaging of microglia by targeting macrophage colony-stimulating factor 1 receptor (CSF1R). Proc Natl Acad Sci USA. 2019;116:1686–91.

pubmed: 30635412 pmcid: 6358677 doi: 10.1073/pnas.1812155116

Mathews WB, Wu Y, Horti AG, Naik R, Hall AW, Holt DP, et al. Radiosynthesis and validation of [5-cyano-N-(4-(4-[(11) C]methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl) furan-2-carboxamide] ([(11) C]CPPC), a PET radiotracer for imaging CSF1R, a microglia-specific marker. J Labelled Comp Radiopharm. 2019;62:903–8.

Coughlin JM, Du Y, Lesniak WG, Harrington CK, Brosnan MK, O’Toole R, et al. First-in-human use of (11)C-CPPC with positron emission tomography for imaging the macrophage colony-stimulating factor 1 receptor. EJNMMI Res. 2022;12:64.

pubmed: 36175737 pmcid: 9522955 doi: 10.1186/s13550-022-00929-4

Knight AC, Varlow C, Zi T, Liang SH, Josephson L, Schmidt K, et al. In vitro evaluation of [(3)H]CPPC as a tool radioligand for CSF-1R. ACS Chem Neurosci. 2021;12:998–1006.

pubmed: 33667059 doi: 10.1021/acschemneuro.0c00802

Rubin LH, Du Y, Sweeney SE, O’Toole R, Harrington CK, Jenkins K, et al. Pilot imaging of the colony stimulating factor 1 receptor in the brains of virally-suppressed individuals with HIV. AIDS. 2023;37:1419–24.

pubmed: 37070549 doi: 10.1097/QAD.0000000000003572

Venneti S, Wang G, Wiley CA. Activated macrophages in HIV encephalitis and a macaque model show increased [3H](R)-PK11195 binding in a PI3-kinase-dependent manner. Neurosci Lett. 2007;426:117–22.

pubmed: 17888571 pmcid: 2083646 doi: 10.1016/j.neulet.2007.08.053

Garvey LJ, Pavese N, Ramlackhansingh A, Thomson E, Allsop JM, Politis M, et al. Acute HCV/HIV coinfection is associated with cognitive dysfunction and cerebral metabolite disturbance, but not increased microglial cell activation. PLoS ONE. 2012;7:e38980.

pubmed: 22808022 pmcid: 3395624 doi: 10.1371/journal.pone.0038980

Coughlin JM, Wang Y, Ma S, Yue C, Kim PK, Adams AV, et al. Regional brain distribution of translocator protein using [(11)C]DPA-713 PET in individuals infected with HIV. J Neurovirol. 2014;20:219–32.

pubmed: 24567030 pmcid: 4078660 doi: 10.1007/s13365-014-0239-5

Garvey LJ, Pavese N, Politis M, Ramlackhansingh A, Brooks DJ, Taylor-Robinson SD, et al. Increased microglia activation in neurologically asymptomatic HIV-infected patients receiving effective ART. AIDS. 2014;28:67–72.

pubmed: 23887068 doi: 10.1097/01.aids.0000432467.54003.f7

Vera JH, Guo Q, Cole JH, Boasso A, Greathead L, Kelleher P, et al. Neuroinflammation in treated HIV-positive individuals: a TSPO PET study. Neurology. 2016;86:1425–32.

pubmed: 26911637 pmcid: 4831035 doi: 10.1212/WNL.0000000000002485

Rubin LH, Sacktor N, Creighton J, Du Y, Endres CJ, Pomper MG, et al. Microglial activation is inversely associated with cognition in individuals living with HIV on effective antiretroviral therapy. AIDS. 2018;32:1661–7.

pubmed: 29746297 doi: 10.1097/QAD.0000000000001858

Boerwinkle AH, Strain JF, Burdo T, Doyle J, Christensen J, Su Y, et al. Comparison of [11C]-PBR28 binding between persons living with HIV and HIV-uninfected individuals. J Acquir Immune Defic Syndr. 2020;85:244–51.

pubmed: 32658129 pmcid: 8053041 doi: 10.1097/QAI.0000000000002435

Zhou X, Ji B, Seki C, Nagai Y, Minamimoto T, Fujinaga M, et al. PET imaging of colony-stimulating factor 1 receptor: A head-to-head comparison of a novel radioligand, (11)C-GW2580, and (11)C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey. J Cereb Blood Flow Metab. 2021;41:2410–22.

pubmed: 33757319 pmcid: 8393303 doi: 10.1177/0271678X211004146

Altomonte S, Yan X, Morse CL, Liow JS, Jenkins MD, Montero Santamaria JA, et al. Discovery of a high-affinity fluoromethyl analog of [(11)C]5-Cyano-N-(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([(11)C]CPPC) and their comparison in mouse and monkey as colony-stimulating factor 1 receptor positron emission tomography radioligands. ACS Pharmacol Transl Sci. 2023;6:614–32.

pubmed: 37082755 pmcid: 10111626 doi: 10.1021/acsptsci.3c00003

van der Wildt B, Nezam M, Kooijman EJM, Reyes ST, Shen B, Windhorst AD, et al. Evaluation of carbon-11 labeled 5-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)nicotinamide as PET tracer for imaging of CSF-1R expression in the brain. Bioorg Med Chem. 2021;42:116245.

pubmed: 34119698 doi: 10.1016/j.bmc.2021.116245

van der Wildt B, Klockow JL, Miao Z, Reyes ST, Park JH, Shen B, et al. Discovery of a CSF-1R inhibitor and PET tracer for imaging of microglia and macrophages in the brain. Nucl Med Biol. 2022;114-115:99–107.

pubmed: 36371938 doi: 10.1016/j.nucmedbio.2022.10.003

Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013;19:1264–72.

pubmed: 24056773 pmcid: 3840724 doi: 10.1038/nm.3337

Ramachandran SA, Jadhavar PS, Miglani SK, Singh MP, Kalane DP, Agarwal AK, et al. Design, synthesis and optimization of bis-amide derivatives as CSF1R inhibitors. Bioorg Med Chem Lett. 2017;27:2153–60.

pubmed: 28377059 doi: 10.1016/j.bmcl.2017.03.064

Lee H, Park JH, Kim H, Woo SK, Choi JY, Lee KH, et al. Synthesis and evaluation of a (18)F-labeled ligand for PET imaging of colony-stimulating factor 1 receptor. Pharmaceuticals (Basel). 2022;15:276.

An X, Wang J, Tong L, Zhang X, Fu H, Zhang J.et al. (18)F-Labeled o‑aminopyridyl alkynyl radioligands targeting colony-stimulating factor 1 receptor for neuroinflammation imaging. Bioorg Med Chem. 2023;83:117233.

Xie Z, Wu B, Liu Y, Ren W, Tong L, Xiang C, et al. Novel class of colony-stimulating factor 1 receptor kinase inhibitors based on an o-aminopyridyl alkynyl scaffold as potential treatment for inflammatory disorders. J Med Chem. 2020;63:1397–414.

pubmed: 31934767 doi: 10.1021/acs.jmedchem.9b01912

Ghazanfari N, van Waarde A, Dierckx R, Doorduin J, de Vries EFJ. Is cyclooxygenase-1 involved in neuroinflammation? J Neurosci Res. 2021;99:2976–98.

pubmed: 34346520 pmcid: 9542093 doi: 10.1002/jnr.24934

McCarthy TJ, Sheriff AU, Graneto MJ, Talley JJ, Welch MJ. Radiosynthesis, in vitro validation, and in vivo evaluation of 18F-labeled COX-1 and COX-2 inhibitors. J Nucl Med. 2002;43:117–24.

pubmed: 11801714

Prabhakaran J, Underwood MD, Parsey RV, Arango V, Majo VJ, Simpson NR, et al. Synthesis and in vivo evaluation of [18F]-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide as a PET imaging probe for COX-2 expression. Bioorg Med Chem. 2007;15:1802–7.

Ji B, Kumata K, Onoe H, Kaneko H, Zhang MR, Seki C, et al. Assessment of radioligands for PET imaging of cyclooxygenase-2 in an ischemic neuronal injury model. Brain Res. 2013;1533:152–62.

pubmed: 23973859 doi: 10.1016/j.brainres.2013.08.026

Kumar JSD, Bai B, Zanderigo F, DeLorenzo C, Prabhakaran J, Parsey RV, et al. In vivo brain imaging, biodistribution, and radiation dosimetry estimation of [(11)C]Celecoxib, a COX-2 PET ligand, in nonhuman primates. Molecules. 2018;23:1929.

de Vries EF, Doorduin J, Dierckx RA, van Waarde A. Evaluation of [(11)C]rofecoxib as PET tracer for cyclooxygenase 2 overexpression in rat models of inflammation. Nucl Med Biol. 2008;35:35–42.

pubmed: 18158941 doi: 10.1016/j.nucmedbio.2007.07.015

Toyokuni T, Kumar JS, Walsh JC, Shapiro A, Talley JJ, Phelps ME, et al. Synthesis of 4-(5-[18F]fluoromethyl-3-phenylisoxazol-4-yl)benzenesulfonamide, a new [18F]fluorinated analogue of valdecoxib, as a potential radiotracer for imaging cyclooxygenase-2 with positron emission tomography. Bioorg Med Chem Lett. 2005;15:4699–702.

pubmed: 16153836 doi: 10.1016/j.bmcl.2005.07.065

Prabhakaran J, Underwood M, Zanderigo F, Simpson NR, Cooper AR, Matthew J, et al. Radiosynthesis and in vivo evaluation of [(11)C]MOV as a PET imaging agent for COX-2. Bioorg Med Chem Lett. 2018;28:2432–5.

pubmed: 29929881 doi: 10.1016/j.bmcl.2018.06.015

Yamamoto Y, Toyohara J, Ishiwata K, Sano K, Yamamoto F, Mukai T, et al. (1)C-labeled analogs of indomethacin esters and amides for brain cyclooxygenase-2 imaging: radiosynthesis, in vitro evaluation and in vivo characteristics in mice. Chem Pharm Bull (Tokyo). 2011;59:938–46.

Yamamoto Y, Tago T, Toyohara J, Saito Y, Yamamoto F. Radiosynthesis and in vivo and ex vivo evaluation of isomeric [(11)C]methoxy analogs of nimesulide as brain cyclooxygenase-2-targeted imaging agents. Biol Pharm Bull. 2022;45:94–103.

pubmed: 34980783 doi: 10.1248/bpb.b21-00608

Elie J, Vercouillie J, Arlicot N, Lemaire L, Bidault R, Bodard S, et al. Design of selective COX-2 inhibitors in the (aza)indazole series. Chemistry, in vitro studies, radiochemistry and evaluations in rats of a [(18)F] PET tracer. J Enzyme Inhib Med Chem. 2019;34:1–7.

pubmed: 30362376 doi: 10.1080/14756366.2018.1501043

Cortes-Salva MY, Shrestha S, Singh P, Morse CL, Jenko KJ, Montero Santamaria JA et al. 2-(4-methylsulfonylphenyl)pyrimidines as prospective radioligands for imaging cyclooxygenase-2 with PET-synthesis, triage, and radiolabeling. Molecules. 2018;23:2850.

Kim MJ, Shrestha SS, Cortes M, Singh P, Morse C, Liow JS, et al. Evaluation of two potent and selective PET radioligands to image COX-1 and COX-2 in rhesus monkeys. J Nucl Med. 2018;59:1907–12.

pubmed: 29959215 pmcid: 6278897 doi: 10.2967/jnumed.118.211144

Shrestha S, Kim MJ, Eldridge M, Lehmann ML, Frankland M, Liow JS, et al. PET measurement of cyclooxygenase-2 using a novel radioligand: upregulation in primate neuroinflammation and first-in-human study. J Neuroinflammation. 2020;17:140.

pubmed: 32359360 pmcid: 7195739 doi: 10.1186/s12974-020-01804-6

Kumar JSD, Zanderigo F, Prabhakaran J, Rubin-Falcone H, Parsey RV, Mann JJ. In vivo evaluation of [(11)C]TMI, a COX-2 selective PET tracer, in baboons. Bioorg Med Chem Lett. 2018;28:3592–5.

pubmed: 30396759 doi: 10.1016/j.bmcl.2018.10.049

Prabhakaran J, Molotkov A, Mintz A, Mann JJ. Progress in PET imaging of neuroinflammation targeting COX-2 enzyme. Molecules. 2021;26:3208.

Shukuri M, Takashima-Hirano M, Tokuda K, Takashima T, Matsumura K, Inoue O, et al. In vivo expression of cyclooxygenase-1 in activated microglia and macrophages during neuroinflammation visualized by PET with 11C-ketoprofen methyl ester. J Nucl Med. 2011;52:1094–101.

pubmed: 21680698 doi: 10.2967/jnumed.110.084046

Shukuri M, Mawatari A, Ohno M, Suzuki M, Doi H, Watanabe Y, et al. Detection of cyclooxygenase-1 in activated microglia during amyloid plaque progression: PET studies in Alzheimer’s disease model mice. J Nucl Med. 2016;57:291–6.

pubmed: 26585055 doi: 10.2967/jnumed.115.166116

Shukuri M, Mawatari A, Takatani S, Tahara T, Inoue M, Arakaki W, et al. Synthesis and preclinical evaluation of (18)F-labeled ketoprofen methyl esters for cyclooxygenase-1 imaging in neuroinflammation. J Nucl Med. 2022;63:1761–7.

pubmed: 35332095 pmcid: 9635687

Singh P, Shrestha S, Cortes-Salva MY, Jenko KJ, Zoghbi SS, Morse CL, et al. 3-Substituted 1,5-Diaryl-1 H-1,2,4-triazoles as prospective PEt radioligands for imaging brain COX-1 in Monkey. Part 1: synthesis and pharmacology. ACS Chem Neurosci. 2018;9:2610–9.

pubmed: 29678105 doi: 10.1021/acschemneuro.8b00102

Shrestha S, Singh P, Cortes-Salva MY, Jenko KJ, Ikawa M, Kim MJ, et al. 3-substituted 1,5-Diaryl-1 H-1,2,4-triazoles as prospective PET radioligands for imaging brain COX-1 in Monkey. Part 2: Selection and evaluation of [(11)C]PS13 for quantitative imaging. ACS Chem Neurosci. 2018;9:2620–7.

pubmed: 29792035 doi: 10.1021/acschemneuro.8b00103

Kim MJ, Lee JH, Juarez Anaya F, Hong J, Miller W, Telu S, et al. First-in-human evaluation of [(11)C]PS13, a novel PET radioligand, to quantify cyclooxygenase-1 in the brain. Eur J Nucl Med Mol Imaging. 2020;47:3143–51.

pubmed: 32399622 pmcid: 8261645 doi: 10.1007/s00259-020-04855-2

Kim MJ, Anaya FJ, Manly LS, Lee JH, Hong J, Shrestha S, et al. Whole-body PET imaging in humans shows that (11)C-PS13 is selective for cyclooxygenase-1 and can measure the in vivo potency of nonsteroidal antiinflammatory drugs. J Nucl Med. 2023;64:159–64.

pubmed: 35798558 pmcid: 9841251 doi: 10.2967/jnumed.122.264061

Taddei C, Morse CL, Kim MJ, Liow JS, Montero Santamaria J, Zhang A, et al. Synthesis of [(18)F]PS13 and evaluation as a PET radioligand for cyclooxygenase-1 in Monkey. ACS Chem Neurosci. 2021;12:517–30.

pubmed: 33491441 doi: 10.1021/acschemneuro.0c00737

Escartin C, Galea E, Lakatos A, O’Callaghan JP, Petzold GC, Serrano-Pozo A, et al. Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci. 2021;24:312–25.

pubmed: 33589835 pmcid: 8007081 doi: 10.1038/s41593-020-00783-4

Westlund KN, Denney RM, Kochersperger LM, Rose RM, Abell CW. Distinct monoamine oxidase A and B populations in primate brain. Science. 1985;230:181–3.

pubmed: 3875898 doi: 10.1126/science.3875898

Fowler JS, MacGregor RR, Wolf AP, Arnett CD, Dewey SL, Schlyer D, et al. Mapping human brain monoamine oxidase A and B with 11C-labeled suicide inactivators and PET. Science. 1987;235:481–5.

pubmed: 3099392 doi: 10.1126/science.3099392

Fowler JS, Logan J, Volkow ND, Wang GJ, MacGregor RR, Ding YS. Monoamine oxidase: radiotracer development and human studies. Methods. 2002;27:263–77.

pubmed: 12183115 doi: 10.1016/S1046-2023(02)00083-X

Fowler JS, Wang GJ, Logan J, Xie S, Volkow ND, MacGregor RR, et al. Selective reduction of radiotracer trapping by deuterium substitution: comparison of carbon-11-L-deprenyl and carbon-11-deprenyl-D2 for MAO B mapping. J Nucl Med. 1995;36:1255–62.

pubmed: 7790952

Kumlien E, Bergstrom M, Lilja A, Andersson J, Szekeres V, Westerberg CE, et al. Positron emission tomography with [11C]deuterium-deprenyl in temporal lobe epilepsy. Epilepsia. 1995;36:712–21.

pubmed: 7555990 doi: 10.1111/j.1528-1157.1995.tb01051.x

Bergstrom M, Kumlien E, Lilja A, Tyrefors N, Westerberg G, Langstrom B. Temporal lobe epilepsy visualized with PET with 11C-L-deuterium-deprenyl-analysis of kinetic data. Acta Neurol Scand. 1998;98:224–31.

pubmed: 9808270 doi: 10.1111/j.1600-0404.1998.tb07300.x

Kumlien E, Nilsson A, Hagberg G, Langstrom B, Bergstrom M. PET with 11C-deuterium-deprenyl and 18F-FDG in focal epilepsy. Acta Neurol Scand. 2001;103:360–6.

pubmed: 11421848 doi: 10.1034/j.1600-0404.2001.103006360.x

Fowler JS, Volkow ND, Cilento R, Wang GJ, Felder C, Logan J. Comparison of brain glucose metabolism and monoamine oxidase B (MAO B) in traumatic brain injury. Clin Positron Imaging. 1999;2:71–79.

pubmed: 14516543 doi: 10.1016/S1095-0397(99)00010-2

Ekblom J, Jossan SS, Gillberg PG, Oreland L, Aquilonius SM. Monoamine oxidase-B in motor cortex: changes in amyotrophic lateral sclerosis. Neuroscience. 1992;49:763–9.

pubmed: 1436479 doi: 10.1016/0306-4522(92)90354-5

Aquilonius SM, Jossan SS, Ekblom JG, Askmark H, Gillberg PG. Increased binding of 3H-L-deprenyl in spinal cords from patients with amyotrophic lateral sclerosis as demonstrated by autoradiography. J Neural Transm Gen Sect. 1992;89:111–22.

pubmed: 1418862 doi: 10.1007/BF01245357

Ekblom J, Jossan SS, Bergstrom M, Oreland L, Walum E, Aquilonius SM. Monoamine oxidase-B in astrocytes. Glia. 1993;8:122–32.

pubmed: 8406673 doi: 10.1002/glia.440080208

Johansson A, Engler H, Blomquist G, Scott B, Wall A, Aquilonius SM, et al. Evidence for astrocytosis in ALS demonstrated by [11C](L)-deprenyl-D2 PET. J Neurol Sci. 2007;255:17–22.

pubmed: 17346749 doi: 10.1016/j.jns.2007.01.057

Fowler JS, Volkow ND, Wang GJ, Logan J, Pappas N, Shea C, et al. Age-related increases in brain monoamine oxidase B in living healthy human subjects. Neurobiol Aging. 1997;18:431–5.

pubmed: 9330975 doi: 10.1016/S0197-4580(97)00037-7

Arakawa R, Stenkrona P, Takano A, Nag S, Maior RS, Halldin C. Test-retest reproducibility of [(11)C]-L-deprenyl-D(2) binding to MAO-B in the human brain. EJNMMI Res. 2017;7:54.

pubmed: 28634836 pmcid: 5478550 doi: 10.1186/s13550-017-0301-4

Varnas K, Finnema SJ, Johnstrom P, Arakawa R, Halldin C, Eriksson LI, et al. Effects of sevoflurane anaesthesia on radioligand binding to monoamine oxidase-B in vivo. Br J Anaesth. 2021;126:238–44.

pubmed: 33036760 doi: 10.1016/j.bja.2020.08.052

Gulyas B, Pavlova E, Kasa P, Gulya K, Bakota L, Varszegi S, et al. Activated MAO-B in the brain of Alzheimer patients, demonstrated by [11C]-L-deprenyl using whole hemisphere autoradiography. Neurochem Int. 2011;58:60–68.

pubmed: 21075154 doi: 10.1016/j.neuint.2010.10.013

Kadir A, Marutle A, Gonzalez D, Scholl M, Almkvist O, Mousavi M, et al. Positron emission tomography imaging and clinical progression in relation to molecular pathology in the first Pittsburgh Compound B positron emission tomography patient with Alzheimer’s disease. Brain. 2011;134:301–17.

pubmed: 21149866 doi: 10.1093/brain/awq349

Farid K, Carter SF, Rodriguez-Vieitez E, Almkvist O, Andersen P, Wall A, et al. Case report of complex amyotrophic lateral sclerosis with cognitive impairment and cortical amyloid deposition. J Alzheimers Dis. 2015;47:661–7.

pubmed: 26401701 doi: 10.3233/JAD-141965

Kumar A, Fontana IC, Nordberg A. Reactive astrogliosis: a friend or foe in the pathogenesis of Alzheimer’s disease. J Neurochem. 2023;164:309–24.

pubmed: 34931315 doi: 10.1111/jnc.15565

Santillo AF, Gambini JP, Lannfelt L, Langstrom B, Ulla-Marja L, Kilander L, et al. In vivo imaging of astrocytosis in Alzheimer’s disease: an (1)(1)C-L-deuteriodeprenyl and PIB PET study. Eur J Nucl Med Mol Imaging. 2011;38:2202–8.

pubmed: 21853308 doi: 10.1007/s00259-011-1895-9

Rodriguez-Vieitez E, Ni R, Gulyas B, Toth M, Haggkvist J, Halldin C, et al. Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study. Eur J Nucl Med Mol Imaging. 2015;42:1119–32.

pubmed: 25893384 pmcid: 4424277 doi: 10.1007/s00259-015-3047-0

Carter SF, Scholl M, Almkvist O, Wall A, Engler H, Langstrom B, et al. Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-L-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. J Nucl Med. 2012;53:37–46.

pubmed: 22213821 doi: 10.2967/jnumed.110.087031

Choo IL, Carter SF, Scholl ML, Nordberg A. Astrocytosis measured by (1)(1)C-deprenyl PET correlates with decrease in gray matter density in the parahippocampus of prodromal Alzheimer’s patients. Eur J Nucl Med Mol Imaging. 2014;41:2120–6.

pubmed: 25077930 doi: 10.1007/s00259-014-2859-7

Scholl M, Carter SF, Westman E, Rodriguez-Vieitez E, Almkvist O, Thordardottir S, et al. Early astrocytosis in autosomal dominant Alzheimer’s disease measured in vivo by multi-tracer positron emission tomography. Sci Rep. 2015;5:16404.

pubmed: 26553227 pmcid: 4639762 doi: 10.1038/srep16404

Rodriguez-Vieitez E, Saint-Aubert L, Carter SF, Almkvist O, Farid K, Scholl M, et al. Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer’s disease. Brain. 2016;139:922–36.

pubmed: 26813969 pmcid: 4766380 doi: 10.1093/brain/awv404

Carter SF, Chiotis K, Nordberg A, Rodriguez-Vieitez E. Longitudinal association between astrocyte function and glucose metabolism in autosomal dominant Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2019;46:348–56.

pubmed: 30515545 doi: 10.1007/s00259-018-4217-7

Vilaplana E, Rodriguez-Vieitez E, Ferreira D, Montal V, Almkvist O, Wall A, et al. Cortical microstructural correlates of astrocytosis in autosomal-dominant Alzheimer disease. Neurology. 2020;94:e2026–e2036.

pubmed: 32291295 pmcid: 7282881 doi: 10.1212/WNL.0000000000009405

Lemoine L, Gillberg PG, Bogdanovic N, Nennesmo I, Saint-Aubert L, Viitanen M, et al. Amyloid, tau, and astrocyte pathology in autosomal-dominant Alzheimer’s disease variants: AbetaPParc and PSEN1DE9. Mol Psychiatry. 2021;26:5609–19.

pubmed: 32581318 doi: 10.1038/s41380-020-0817-2

Ni R, Rojdner J, Voytenko L, Dyrks T, Thiele A, Marutle A, et al. In vitro characterization of the regional binding distribution of amyloid PET tracer florbetaben and the glia tracers deprenyl and PK11195 in autopsy Alzheimer’s brain tissue. J Alzheimers Dis. 2021;80:1723–37.

pubmed: 33749648 pmcid: 8150513 doi: 10.3233/JAD-201344

Marutle A, Gillberg PG, Bergfors A, Yu W, Ni R, Nennesmo I.et al. (3)H-deprenyl and (3)H-PIB autoradiography show different laminar distributions of astroglia and fibrillar beta-amyloid in Alzheimer brain. J Neuroinflammation. 2013;10:90.

Lemoine L, Saint-Aubert L, Nennesmo I, Gillberg PG, Nordberg A. Cortical laminar tau deposits and activated astrocytes in Alzheimer’s disease visualised by (3)H-THK5117 and (3)H-deprenyl autoradiography. Sci Rep. 2017;7:45496.

pubmed: 28374768 pmcid: 5379625 doi: 10.1038/srep45496

Hirvonen J, Kailajarvi M, Haltia T, Koskimies S, Nagren K, Virsu P, et al. Assessment of MAO-B occupancy in the brain with PET and [11C]-L-deprenyl-D2: a dose-finding study with a novel MAO-B inhibitor, EVT 301. Clin Pharmacol Ther. 2009;85:506–12.

pubmed: 19129751 doi: 10.1038/clpt.2008.241

Sturm S, Forsberg A, Nave S, Stenkrona P, Seneca N, Varrone A, et al. Positron emission tomography measurement of brain MAO-B inhibition in patients with Alzheimer’s disease and elderly controls after oral administration of sembragiline. Eur J Nucl Med Mol Imaging. 2017;44:382–91.

pubmed: 27633250 doi: 10.1007/s00259-016-3510-6

Nag S, Lehmann L, Heinrich T, Thiele A, Kettschau G, Nakao R, et al. Synthesis of three novel fluorine-18 labeled analogues of L-deprenyl for positron emission tomography (PET) studies of monoamine oxidase B (MAO-B). J Med Chem. 2011;54:7023–9.

pubmed: 21923198 doi: 10.1021/jm200710b

Nag S, Varrone A, Toth M, Thiele A, Kettschau G, Heinrich T, et al. In vivo evaluation in cynomolgus monkey brain and metabolism of [(1)(8)F]fluorodeprenyl: a new MAO-B pet radioligand. Synapse. 2012;66:323–30.

pubmed: 22124971 doi: 10.1002/syn.21514

Nag S, Fazio P, Lehmann L, Kettschau G, Heinrich T, Thiele A, et al. In vivo and in vitro characterization of a novel MAO-B inhibitor radioligand, 18F-labeled deuterated fluorodeprenyl. J Nucl Med. 2016;57:315–20.

pubmed: 26585057 doi: 10.2967/jnumed.115.161083

Ballweg A, Klaus C, Vogler L, Katzdobler S, Wind K, Zatcepin A.et al. (18)F]F-DED PET imaging of reactive astrogliosis in neurodegenerative diseases: preclinical proof of concept and first-in-human data. J Neuroinflammation. 2023;20:68.

Vasdev N, Sadovski O, Moran MD, Parkes J, Meyer JH, Houle S, et al. Development of new radiopharmaceuticals for imaging monoamine oxidase B. Nucl Med Biol. 2011;38:933–43.

pubmed: 21982565 doi: 10.1016/j.nucmedbio.2011.03.003

Dukic-Stefanovic S, Hang Lai T, Toussaint M, Clauss O, Jevtic II, Penjisevic JZ, et al. In vitro and in vivo evaluation of fluorinated indanone derivatives as potential positron emission tomography agents for the imaging of monoamine oxidase B in the brain. Bioorg Med Chem Lett. 2021;48:128254.

pubmed: 34256118 doi: 10.1016/j.bmcl.2021.128254

Nag S, Lehmann L, Kettschau G, Heinrich T, Thiele A, Varrone A, et al. Synthesis and evaluation of [(1)(8)F]fluororasagiline, a novel positron emission tomography (PET) radioligand for monoamine oxidase B (MAO-B). Bioorg Med Chem. 2012;20:3065–71.

pubmed: 22436387 doi: 10.1016/j.bmc.2012.02.056

Nag S, Lehmann L, Kettschau G, Toth M, Heinrich T, Thiele A, et al. Development of a novel fluorine-18 labeled deuterated fluororasagiline ([(18)F]fluororasagiline-D2) radioligand for PET studies of monoamino oxidase B (MAO-B). Bioorg Med Chem. 2013;21:6634–41.

pubmed: 24012376 doi: 10.1016/j.bmc.2013.08.019

Harada R, Hayakawa Y, Ezura M, Lerdsirisuk P, Du Y, Ishikawa Y, et al. (18)F-SMBT-1: a selective and reversible PET tracer for monoamine oxidase-B imaging. J Nucl Med. 2021;62:253–8.

Villemagne VL, Harada R, Dore V, Furumoto S, Mulligan R, Kudo Y, et al. First-in-humans evaluation of (18)F-SMBT-1, a Novel (18)F-labeled monoamine oxidase-B PET tracer for imaging reactive astrogliosis. J Nucl Med. 2022;63:1551–9.

pubmed: 35086898 pmcid: 9536703 doi: 10.2967/jnumed.121.263254

Villemagne VL, Harada R, Dore V, Furumoto S, Mulligan R, Kudo Y, et al. Assessing reactive astrogliosis with (18)F-SMBT-1 across the Alzheimer disease spectrum. J Nucl Med. 2022;63:1560–9.

pubmed: 35086892 pmcid: 9536709 doi: 10.2967/jnumed.121.263255

Olsen M, Aguilar X, Sehlin D, Fang XT, Antoni G, Erlandsson A, et al. Astroglial responses to amyloid-beta progression in a mouse model of Alzheimer’s disease. Mol Imaging Biol. 2018;20:605–14.

pubmed: 29297157 doi: 10.1007/s11307-017-1153-z

Chatterjee P, Dore V, Pedrini S, Krishnadas N, Thota R, Bourgeat P, et al. Plasma glial fibrillary acidic protein is associated with 18F-SMBT-1 PET: two putative astrocyte reactivity biomarkers for Alzheimer’s disease. J Alzheimers Dis. 2023;92:615–28.

pubmed: 36776057 pmcid: 10041433 doi: 10.3233/JAD-220908

Dahl K, Bernard-Gauthier V, Nag S, Varnas K, Narayanaswami V, Mahdi Moein M, et al. Synthesis and preclinical evaluation of [(18)F]FSL25.1188, a reversible PET radioligand for monoamine oxidase-B. Bioorg Med Chem Lett. 2019;29:1624–7.

pubmed: 31060887 doi: 10.1016/j.bmcl.2019.04.040

Hicks JW, Sadovski O, Parkes J, Houle S, Hay BA, Carter RL, et al. Radiosynthesis and ex vivo evaluation of [(18)F]-(S)-3-(6-(3-fluoropropoxy)benzo[d]isoxazol-3-yl)-5-(methoxymethyl)oxazolidin-2-one for imaging MAO-B with PET. Bioorg Med Chem Lett. 2015;25:288–91.

pubmed: 25488845 doi: 10.1016/j.bmcl.2014.11.048

Saba W, Valette H, Peyronneau MA, Bramoulle Y, Coulon C, Curet O, et al. (11)C]SL25.1188, a new reversible radioligand to study the monoamine oxidase type B with PET: preclinical characterisation in nonhuman primate. Synapse. 2010;64:61–69.

Rusjan PM, Wilson AA, Miler L, Fan I, Mizrahi R, Houle S, et al. Kinetic modeling of the monoamine oxidase B radioligand [(1)(1)C]SL25.1188 in human brain with high-resolution positron emission tomography. J Cereb Blood Flow Metab. 2014;34:883–9.

pubmed: 24517979 pmcid: 4013770 doi: 10.1038/jcbfm.2014.34

Moriguchi S, Wilson AA, Miler L, Rusjan PM, Vasdev N, Kish SJ, et al. Monoamine oxidase B total distribution volume in the prefrontal cortex of major depressive disorder: an [11C]SL25.1188 positron emission tomography study. JAMA Psychiatry. 2019;76:634–41.

pubmed: 30840042 pmcid: 6551845 doi: 10.1001/jamapsychiatry.2019.0044

Gill T, Watling SE, Richardson JD, McCluskey T, Tong J, Meyer JH, et al. Imaging of astrocytes in posttraumatic stress disorder: A PET study with the monoamine oxidase B radioligand [(11)C]SL25.1188. Eur Neuropsychopharmacol. 2022;54:54–61.

pubmed: 34773851 doi: 10.1016/j.euroneuro.2021.10.006

Varnas K, Cselenyi Z, Arakawa R, Nag S, Stepanov V, Moein MM, et al. The pro-psychotic metabotropic glutamate receptor compounds fenobam and AZD9272 share binding sites with monoamine oxidase-B inhibitors in humans. Neuropharmacology. 2020;162:107809.

pubmed: 31589885 doi: 10.1016/j.neuropharm.2019.107809

Koshimori Y, Cusimano MD, Vieira EL, Rusjan PM, Kish SJ, Vasdev N, et al. Astrogliosis marker 11C-SL25.1188 PET in traumatic brain injury with persistent symptoms. Brain. 2023;146:4469–75.

pubmed: 37602426 pmcid: 10629767 doi: 10.1093/brain/awad279

Nag S, Jia Z, Svedberg M, Jackson A, Ahmad R, Luthra S, et al. Synthesis and autoradiography of novel F-18 labeled reversible radioligands for detection of monoamine oxidase B. ACS Chem Neurosci. 2020;11:4398–404.

pubmed: 33284012 doi: 10.1021/acschemneuro.0c00631

Varnas K, Nag S, Halldin C, Farde L. PET evaluation of the novel F-18 labeled reversible radioligand [(18)F]GEH200449 for detection of monoamine oxidase-B in the non-human primate brain. ACS Chem Neurosci. 2023;14:3206–11.

pubmed: 37587571 doi: 10.1021/acschemneuro.3c00332

Ruiz J, Martin I, Callado LF, Meana JJ, Barturen F, Garcia-Sevilla JA. Non-adrenoceptor [3H]idazoxan binding sites (I2-imidazoline sites) are increased in postmortem brain from patients with Alzheimer’s disease. Neurosci Lett. 1993;160:109–12.

pubmed: 7902542 doi: 10.1016/0304-3940(93)90925-B

Qiu WW, Zheng RY. Neuroprotective effects of receptor imidazoline 2 and its endogenous ligand agmatine. Neurosci Bull. 2006;22:187–91.

pubmed: 17704848

Hudson AL, Tyacke RJ, Lalies MD, Davies N, Finn DP, Marti O, et al. Novel ligands for the investigation of imidazoline receptors and their binding proteins. Ann N Y Acad Sci. 2003;1009:302–8.

pubmed: 15028604 doi: 10.1196/annals.1304.039

Saczewski F, Tabin P, Tyacke RJ, Maconie A, Saczewski J, Kornicka A, et al. 2-(4,5-dihydroimidazol-2-yl)benzimidazoles as highly selective imidazoline I2/adrenergic alpha2 receptor ligands. Bioorg Med Chem. 2006;14:6679–85.

pubmed: 16782348 doi: 10.1016/j.bmc.2006.05.062

Tyacke RJ, Fisher A, Robinson ES, Grundt P, Turner EM, Husbands SM, et al. Evaluation and initial in vitro and ex vivo characterization of the potential positron emission tomography ligand, BU99008 (2-(4,5-dihydro-1H-imidazol-2-yl)-1- methyl-1H-indole), for the imidazoline(2) binding site. Synapse. 2012;66:542–51.

pubmed: 22290740 doi: 10.1002/syn.21541

Kealey S, Turner EM, Husbands SM, Salinas CA, Jakobsen S, Tyacke RJ, et al. Imaging imidazoline-I2 binding sites in porcine brain using 11C-BU99008. J Nucl Med. 2013;54:139–44.

pubmed: 23223380 doi: 10.2967/jnumed.112.108258

Parker CA, Nabulsi N, Holden D, Lin SF, Cass T, Labaree D, et al. Evaluation of 11C-BU99008, a PET ligand for the imidazoline2 binding sites in rhesus brain. J Nucl Med. 2014;55:838–44.

pubmed: 24711648 doi: 10.2967/jnumed.113.131854

Tyacke RJ, Myers JFM, Venkataraman A, Mick I, Turton S, Passchier J, et al. Evaluation of (11)C-BU99008, a PET Ligand for the Imidazoline(2) Binding Site in Human Brain. J Nucl Med. 2018;59:1597–602.

pubmed: 29523627 doi: 10.2967/jnumed.118.208009

Venkataraman AV, Keat N, Myers JF, Turton S, Mick I, Gunn RN, et al. First evaluation of PET-based human biodistribution and radiation dosimetry of (11)C-BU99008, a tracer for imaging the imidazoline(2) binding site. EJNMMI Res. 2018;8:71.

pubmed: 30062395 pmcid: 6066589 doi: 10.1186/s13550-018-0429-x

Kumar A, Koistinen NA, Malarte ML, Nennesmo I, Ingelsson M, Ghetti B, et al. Astroglial tracer BU99008 detects multiple binding sites in Alzheimer’s disease brain. Mol Psychiatry. 2021;26:5833–47.

pubmed: 33888872 pmcid: 8758481 doi: 10.1038/s41380-021-01101-5

Livingston NR, Calsolaro V, Hinz R, Nowell J, Raza S, Gentleman S, et al. Relationship between astrocyte reactivity, using novel (11)C-BU99008 PET, and glucose metabolism, grey matter volume and amyloid load in cognitively impaired individuals. Mol Psychiatry. 2022;27:2019–29.

pubmed: 35125495 pmcid: 9126819 doi: 10.1038/s41380-021-01429-y

Calsolaro V, Matthews PM, Donat CK, Livingston NR, Femminella GD, Guedes SS, et al. Astrocyte reactivity with late-onset cognitive impairment assessed in vivo using (11)C-BU99008 PET and its relationship with amyloid load. Mol Psychiatry. 2021;26:5848–55.

pubmed: 34267329 pmcid: 8758500 doi: 10.1038/s41380-021-01193-z

Wilson H, Dervenoulas G, Pagano G, Tyacke RJ, Polychronis S, Myers J, et al. Imidazoline 2 binding sites reflecting astroglia pathology in Parkinson’s disease: an in vivo11C-BU99008 PET study. Brain. 2019;142:3116–28.

pubmed: 31504212 doi: 10.1093/brain/awz260

Mohamed MA, Zeng Z, Gennaro M, Lao-Kaim NP, Myers JFM, Calsolaro V, et al. Astrogliosis in aging and Parkinson’s disease dementia: a new clinical study with (11)C-BU99008 PET. Brain Commun. 2022;4:fcac199.

pubmed: 36072646 pmcid: 9445175 doi: 10.1093/braincomms/fcac199

Kawamura K, Yui J, Konno F, Yamasaki T, Hatori A, Wakizaka H, et al. Synthesis and evaluation of PET probes for the imaging of I2 imidazoline receptors in peripheral tissues. Nucl Med Biol. 2012;39:89–99.

pubmed: 21831654 doi: 10.1016/j.nucmedbio.2011.06.001

Kawamura K, Kimura Y, Yui J, Wakizaka H, Yamasaki T, Hatori A, et al. PET study using [11C]FTIMD with ultra-high specific activity to evaluate I2-imidazoline receptors binding in rat brains. Nucl Med Biol. 2012;39:199–206.

pubmed: 21958848 doi: 10.1016/j.nucmedbio.2011.07.008

Kawamura K, Naganawa M, Konno F, Yui J, Wakizaka H, Yamasaki T, et al. Imaging of I2-imidazoline receptors by small-animal PET using 2-(3-fluoro-[4-11C]tolyl)-4,5-dihydro-1H-imidazole ([11C]FTIMD). Nucl Med Biol. 2010;37:625–35.

Kawamura K, Maeda J, Hatori A, Okauchi T, Nagai Y, Higuchi M, et al. In vivo and in vitro imaging of I(2) imidazoline receptors in the monkey brain. Synapse. 2011;65:452–5.

pubmed: 21370281 doi: 10.1002/syn.20897

Kawamura K, Shimoda Y, Kumata K, Fujinaga M, Yui J, Yamasaki T, et al. In vivo evaluation of a new (1)(8)F-labeled PET ligand, [(1)(8)F]FEBU, for the imaging of I(2)-imidazoline receptors. Nucl Med Biol. 2015;42:406–12.

pubmed: 25583220 doi: 10.1016/j.nucmedbio.2014.12.014

Kawamura K, Yamasaki T, Zhang Y, Wakizaka H, Hatori A, Xie L, et al. Change in the Binding of [(11)C]BU99008 to imidazoline I2 receptor using brain PET in Zucker rats. Mol Imaging Biol. 2019;21:105–12.

pubmed: 29736564 doi: 10.1007/s11307-018-1206-y

Kawamura K, Shimoda Y, Yui J, Zhang Y, Yamasaki T, Wakizaka H, et al. A useful PET probe [(11)C]BU99008 with ultra-high specific radioactivity for small animal PET imaging of I(2)-imidazoline receptors in the hypothalamus. Nucl Med Biol. 2017;45:1–7.

pubmed: 27835825 doi: 10.1016/j.nucmedbio.2016.10.005

Brunt TM, Bossong MG. The neuropharmacology of cannabinoid receptor ligands in central signaling pathways. Eur J Neurosci. 2022;55:909–21.

pubmed: 32974975 doi: 10.1111/ejn.14982

Komorowska-Muller JA, Schmole AC. CB2 receptor in microglia: the guardian of self-control. Int J Mol Sci. 2020;22:19.

Di Marzo V, Stella N, Zimmer A. Endocannabinoid signalling and the deteriorating brain. Nat Rev Neurosci. 2015;16:30–42.

pubmed: 25524120 pmcid: 4471876 doi: 10.1038/nrn3876

Grabon W, Bodennec J, Rheims S, Belmeguenai A, Bezin L. Update on the controversial identity of cells expressing cnr2 gene in the nervous system. CNS Neurosci Ther. 2023;29:760–70.

pubmed: 36604187 pmcid: 9928557 doi: 10.1111/cns.13977

Onaivi ES. Neuropsychobiological evidence for the functional presence and expression of cannabinoid CB2 receptors in the brain. Neuropsychobiology. 2006;54:231–46.

pubmed: 17356307 doi: 10.1159/000100778

Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, et al. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science. 2005;310:329–32.

pubmed: 16224028 doi: 10.1126/science.1115740

Kibret BG, Ishiguro H, Horiuchi Y, Onaivi ES. New insights and potential therapeutic targeting of CB2 cannabinoid receptors in CNS disorders. Int J Mol Sci. 2022; 23.

García-Gutiérrez MS, Navarrete F, Gasparyan A, Manzanares J. Therapeutic potential of the cannabinoid receptor 2 in neuropsychiatry. Exploration of Neuroprotective Therapy 2021;1: 55–71.

Evens N, Muccioli GG, Houbrechts N, Lambert DM, Verbruggen AM, Van Laere K, et al. Synthesis and biological evaluation of carbon-11- and fluorine-18-labeled 2-oxoquinoline derivatives for type 2 cannabinoid receptor positron emission tomography imaging. Nucl Med Biol. 2009;36:455–65.

pubmed: 19423014 doi: 10.1016/j.nucmedbio.2009.01.009

Evens N, Vandeputte C, Coolen C, Janssen P, Sciot R, Baekelandt V, et al. Preclinical evaluation of [11C]NE40, a type 2 cannabinoid receptor PET tracer. Nucl Med Biol. 2012;39:389–99.

pubmed: 22154685 doi: 10.1016/j.nucmedbio.2011.09.005

Vandeputte C, Casteels C, Struys T, Koole M, van Veghel D, Evens N, et al. Small-animal PET imaging of the type 1 and type 2 cannabinoid receptors in a photothrombotic stroke model. Eur J Nucl Med Mol Imaging. 2012;39:1796–806.

pubmed: 22895861 doi: 10.1007/s00259-012-2209-6

Ahmad R, Koole M, Evens N, Serdons K, Verbruggen A, Bormans G, et al. Whole-body biodistribution and radiation dosimetry of the cannabinoid type 2 receptor ligand [11C]-NE40 in healthy subjects. Mol Imaging Biol. 2013;15:384–90.

pubmed: 23508466 doi: 10.1007/s11307-013-0626-y

Hosoya T, Fukumoto D, Kakiuchi T, Nishiyama S, Yamamoto S, Ohba H, et al. In vivo TSPO and cannabinoid receptor type 2 availability early in post-stroke neuroinflammation in rats: a positron emission tomography study. J Neuroinflammation. 2017;14:69.

pubmed: 28356120 pmcid: 5372312 doi: 10.1186/s12974-017-0851-4

Yamagishi S, Iga Y, Nakamura M, Takizawa C, Fukumoto D, Kakiuchi T, et al. Upregulation of cannabinoid receptor type 2, but not TSPO, in senescence-accelerated neuroinflammation in mice: a positron emission tomography study. J Neuroinflammation. 2019;16:208.

pubmed: 31707986 pmcid: 6842455 doi: 10.1186/s12974-019-1604-3

Ahmad R, Postnov A, Bormans G, Versijpt J, Vandenbulcke M, Van Laere K. Decreased in vivo availability of the cannabinoid type 2 receptor in Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2016;43:2219–27.

pubmed: 27488857 doi: 10.1007/s00259-016-3457-7

Evens N, Bosier B, Lavey BJ, Kozlowski JA, Vermaelen P, Baudemprez L, et al. Labelling and biological evaluation of [(11)C]methoxy-Sch225336: a radioligand for the cannabinoid-type 2 receptor. Nucl Med Biol. 2008;35:793–800.

pubmed: 18848664 doi: 10.1016/j.nucmedbio.2008.07.004

Vandeputte C, Evens N, Toelen J, Deroose CM, Bosier B, Ibrahimi A, et al. A PET brain reporter gene system based on type 2 cannabinoid receptors. J Nucl Med. 2011;52:1102–9.

pubmed: 21680683 doi: 10.2967/jnumed.110.084426

Ahamed M, van Veghel D, Ullmer C, Van Laere K, Verbruggen A, Bormans GM. Synthesis, biodistribution and in vitro evaluation of brain permeable high affinity type 2 cannabinoid receptor agonists [(11)C]MA2 and [(18)F]MA3. Front Neurosci. 2016;10:431.

pubmed: 27713686 pmcid: 5031696 doi: 10.3389/fnins.2016.00431

Evens N, Vandeputte C, Muccioli GG, Lambert DM, Baekelandt V, Verbruggen AM, et al. Synthesis, in vitro and in vivo evaluation of fluorine-18 labelled FE-GW405833 as a PET tracer for type 2 cannabinoid receptor imaging. Bioorg Med Chem. 2011;19:4499–505.

pubmed: 21737287 doi: 10.1016/j.bmc.2011.06.033

Horti AG, Gao Y, Ravert HT, Finley P, Valentine H, Wong DF, et al. Synthesis and biodistribution of [11C]A-836339, a new potential radioligand for PET imaging of cannabinoid type 2 receptors (CB2). Bioorg Med Chem. 2010;18:5202–7.

pubmed: 20554448 pmcid: 2903661 doi: 10.1016/j.bmc.2010.05.058

Savonenko AV, Melnikova T, Wang Y, Ravert H, Gao Y, Koppel J, et al. Cannabinoid CB2 receptors in a mouse model of abeta amyloidosis: immunohistochemical analysis and suitability as a PET biomarker of neuroinflammation. PLoS One. 2015;10:e0129618.

pubmed: 26086915 pmcid: 4472959 doi: 10.1371/journal.pone.0129618

Pottier G, Gomez-Vallejo V, Padro D, Boisgard R, Dolle F, Llop J, et al. PET imaging of cannabinoid type 2 receptors with [(11)C]A-836339 did not evidence changes following neuroinflammation in rats. J Cereb Blood Flow Metab. 2017;37:1163–78.

pubmed: 28079433 pmcid: 5363492 doi: 10.1177/0271678X16685105

Du Y, Coughlin JM, Brosnan MK, Chen A, Shinehouse LK, Abdallah R, et al. First-in-human imaging using [(11)C]MDTC: a radiotracer targeting the cannabinoid receptor type 2. Eur J Nucl Med Mol Imaging. 2023;50:2386–93.

pubmed: 36877235 doi: 10.1007/s00259-023-06170-y

Fujinaga M, Kumata K, Yanamoto K, Kawamura K, Yamasaki T, Yui J, et al. Radiosynthesis of novel carbon-11-labeled triaryl ligands for cannabinoid-type 2 receptor. Bioorg Med Chem Lett. 2010;20:1565–8.

pubmed: 20137936 doi: 10.1016/j.bmcl.2010.01.074

Turkman N, Shavrin A, Paolillo V, Yeh HH, Flores L, Soghomonian S, et al. Synthesis and preliminary evaluation of [18F]-labeled 2-oxoquinoline derivatives for PET imaging of cannabinoid CB2 receptor. Nucl Med Biol. 2012;39:593–600.

pubmed: 22226022 pmcid: 3324652 doi: 10.1016/j.nucmedbio.2011.10.019

Mu L, Bieri D, Slavik R, Drandarov K, Muller A, Cermak S, et al. Radiolabeling and in vitro /in vivo evaluation of N-(1-adamantyl)-8-methoxy-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide as a PET probe for imaging cannabinoid type 2 receptor. J Neurochem. 2013;126:616–24.

pubmed: 23795580 doi: 10.1111/jnc.12354

Lueg C, Schepmann D, Gunther R, Brust P, Wunsch B. Development of fluorinated CB(2) receptor agonists for PET studies. Bioorg Med Chem. 2013;21:7481–98.

pubmed: 24139843 doi: 10.1016/j.bmc.2013.09.040

Slavik R, Bieri D, Cermak S, Muller A, Kramer SD, Weber M, et al. Development and evaluation of novel PET tracers for imaging cannabinoid receptor type 2 in brain. Chimia (Aarau). 2014;68:208–10.

pubmed: 24983598 doi: 10.2533/chimia.2014.208

Haider A, Muller Herde A, Slavik R, Weber M, Mugnaini C, Ligresti A, et al. Synthesis and biological evaluation of thiophene-based cannabinoid receptor type 2 radiotracers for PET imaging. Front Neurosci. 2016;10:350.

pubmed: 27512365 pmcid: 4961704 doi: 10.3389/fnins.2016.00350

Slavik R, Muller Herde A, Haider A, Kramer SD, Weber M, Schibli R, et al. Discovery of a fluorinated 4-oxo-quinoline derivative as a potential positron emission tomography radiotracer for imaging cannabinoid receptor type 2. J Neurochem. 2016;138:874–86.

pubmed: 27385045 doi: 10.1111/jnc.13716

Haider A, Spinelli F, Herde AM, Mu B, Keller C, Margelisch M, et al. Evaluation of 4-oxo-quinoline-based CB2 PET radioligands in R6/2 chorea huntington mouse model and human ALS spinal cord tissue. Eur J Med Chem. 2018;145:746–59.

pubmed: 29353725 doi: 10.1016/j.ejmech.2017.12.097

Haider A, Kretz J, Gobbi L, Ahmed H, Atz K, Burkler M, et al. Structure-activity relationship studies of pyridine-based ligands and identification of a fluorinated derivative for positron emission tomography imaging of cannabinoid type 2 receptors. J Med Chem. 2019;62:11165–81.

pubmed: 31751140 doi: 10.1021/acs.jmedchem.9b01280

Kecheliev V, Spinelli F, Herde A, Haider A, Mu L, Klohs J, et al. Evaluation of cannabinoid type 2 receptor expression and pyridine-based radiotracers in brains from a mouse model of Alzheimer’s disease. Front Aging Neurosci. 2022;14:1018610.

pubmed: 36248003 pmcid: 9561934 doi: 10.3389/fnagi.2022.1018610

Ueberham L, Gundel D, Kellert M, Deuther-Conrad W, Ludwig FA, Lonnecke P, et al. Development of the high-affinity carborane-based cannabinoid receptor type 2 PET ligand [(18)F]LUZ5-d(8). J Med Chem. 2023;66:5242–60.

pubmed: 36944112 pmcid: 10782483 doi: 10.1021/acs.jmedchem.3c00195

Kallinen A, Mardon K, Lane S, Montgomery AP, Bhalla R, Stimson DHR, et al. Synthesis and preclinical evaluation of fluorinated 5-azaindoles as CB2 PET radioligands. ACS Chem Neurosci. 2023;14:2902–21.

pubmed: 37499194 doi: 10.1021/acschemneuro.3c00345

Pascali G, Panetta D, De Simone M, Burchielli S, Lucchesi V, Sanguinetti E, et al. Preliminary investigation of a novel 18F radiopharmaceutical for imaging CB2 Receptors in a SOD Mouse Model. Australian Journal of Chemistry. 2021;74:443–52.

doi: 10.1071/CH20247

Teodoro R, Gundel D, Deuther-Conrad W, Ueberham L, Toussaint M, Bormans G et al. Development of [(18)F]LU14 for PET imaging of cannabinoid receptor type 2 in the brain. Int J Mol Sci. 2021;22:8051.

Gundel D, Deuther-Conrad W, Ueberham L, Kaur S, Otikova E, Teodoro R, et al. Structure-based design, optimization, and development of [(18)F]LU13: a novel radioligand for cannabinoid receptor type 2 imaging in the brain with PET. J Med Chem. 2022;65:9034–49.

pubmed: 35771668 doi: 10.1021/acs.jmedchem.2c00256

Slavik R, Herde AM, Bieri D, Weber M, Schibli R, Kramer SD, et al. Synthesis, radiolabeling and evaluation of novel 4-oxo-quinoline derivatives as PET tracers for imaging cannabinoid type 2 receptor. Eur J Med Chem. 2015;92:554–64.

pubmed: 25599952 doi: 10.1016/j.ejmech.2015.01.028

Slavik R, Grether U, Muller Herde A, Gobbi L, Fingerle J, Ullmer C, et al. Discovery of a high affinity and selective pyridine analog as a potential positron emission tomography imaging agent for cannabinoid type 2 receptor. J Med Chem. 2015;58:4266–77.

pubmed: 25950914 doi: 10.1021/acs.jmedchem.5b00283

Moldovan RP, Teodoro R, Gao Y, Deuther-Conrad W, Kranz M, Wang Y, et al. Development of a high-affinity PET radioligand for imaging cannabinoid subtype 2 receptor. J Med Chem. 2016;59:7840–55.

pubmed: 27500461 doi: 10.1021/acs.jmedchem.6b00554

Ni R, Muller Herde A, Haider A, Keller C, Louloudis G, Vaas M, et al. In vivo imaging of cannabinoid type 2 receptors: functional and structural alterations in mouse model of cerebral ischemia by PET and MRI. Mol Imaging Biol. 2022;24:700–9.

pubmed: 34642898 doi: 10.1007/s11307-021-01655-4

Bravo GA, Cedeno RR, Casadevall MP, Ramio-Torrenta L. Sphingosine-1-phosphate (S1P) and S1P signaling pathway modulators, from current insights to future perspectives. Cells. 2022; 11.

McGinley MP, Cohen JA. Sphingosine 1-phosphate receptor modulators in multiple sclerosis and other conditions. Lancet. 2021;398:1184–94.

pubmed: 34175020 doi: 10.1016/S0140-6736(21)00244-0

Chen H, Wang J, Zhang C, Ding P, Tian S, Chen J, et al. Sphingosine 1-phosphate receptor, a new therapeutic direction in different diseases. Biomed Pharmacother. 2022;153:113341.

pubmed: 35785704 doi: 10.1016/j.biopha.2022.113341

Brinkmann V. FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system. Br J Pharmacol. 2009;158:1173–82.

pubmed: 19814729 pmcid: 2782328 doi: 10.1111/j.1476-5381.2009.00451.x

Briard E, Orain D, Beerli C, Billich A, Streiff M, Bigaud M, et al. BZM055, an iodinated radiotracer candidate for PET and SPECT imaging of myelin and FTY720 brain distribution. ChemMedChem. 2011;6:667–77.

pubmed: 21280229 doi: 10.1002/cmdc.201000477

Rokka J, Federico C, Jurttila J, Snellman A, Haaparanta M, Rinne JO, et al. 19F/18F exchange synthesis for a novel [18F]S1P3-radiopharmaceutical. J Labelled Comp Radiopharm. 2013;56:385–91.

pubmed: 24285478 doi: 10.1002/jlcr.3055

Prasad VP, Wagner S, Keul P, Hermann S, Levkau B, Schafers M, et al. Synthesis of fluorinated analogues of sphingosine-1-phosphate antagonists as potential radiotracers for molecular imaging using positron emission tomography. Bioorg Med Chem. 2014;22:5168–81.

pubmed: 25216968 doi: 10.1016/j.bmc.2014.08.009

Briard E, Rudolph B, Desrayaud S, Krauser JA, Auberson YP. MS565: A SPECT tracer for evaluating the brain penetration of BAF312 (Siponimod). ChemMedChem. 2015;10:1008–18.

pubmed: 25924727 doi: 10.1002/cmdc.201500115

Rosenberg AJ, Liu H, Tu Z. A practical process for the preparation of [(32)P]S1P and binding assay for S1P receptor ligands. Appl Radiat Isot. 2015;102:5–9.

pubmed: 25931137 pmcid: 4457593 doi: 10.1016/j.apradiso.2015.04.010

Liu H, Jin H, Yue X, Luo Z, Liu C, Rosenberg AJ, et al. PET imaging study of S1PR1 expression in a rat model of multiple sclerosis. Mol Imaging Biol. 2016;18:724–32.

pubmed: 26975859 pmcid: 5297893 doi: 10.1007/s11307-016-0944-y

Rosenberg AJ, Liu H, Jin H, Yue X, Riley S, Brown SJ, et al. Design, synthesis, and in vitro and in vivo evaluation of an (18)F-labeled sphingosine 1-phosphate receptor 1 (S1P1) PET Tracer. J Med Chem. 2016;59:6201–20.

pubmed: 27280499 pmcid: 5091660 doi: 10.1021/acs.jmedchem.6b00390

Jin H, Yang H, Liu H, Zhang Y, Zhang X, Rosenberg AJ, et al. A promising carbon-11-labeled sphingosine-1-phosphate receptor 1-specific PET tracer for imaging vascular injury. J Nucl Cardiol. 2017;24:558–70.

pubmed: 26843200 doi: 10.1007/s12350-015-0391-1

Liu H, Jin H, Yue X, Han J, Baum P, Abendschein DR, et al. PET study of sphingosine-1-phosphate receptor 1 expression in response to vascular inflammation in a rat model of carotid injury. Mol Imaging. 2017;16:1536012116689770.

pubmed: 28654378 pmcid: 5470136 doi: 10.1177/1536012116689770

Liu H, Jin H, Han J, Yue X, Yang H, Zayed MA, et al. Upregulated sphingosine 1-phosphate receptor 1 expression in human and murine atherosclerotic plaques. Mol Imaging Biol. 2018;20:448–56.

pubmed: 29134505 pmcid: 5975257 doi: 10.1007/s11307-017-1141-3

Jiang H, Joshi S, Liu H, Mansor S, Qiu L, Zhao H, et al. In vitro and in vivo investigation of S1PR1 expression in the central nervous system using [(3)H]CS1P1 and [(11)C]CS1P1. ACS Chem Neurosci. 2021;12:3733–44.

pubmed: 34516079 doi: 10.1021/acschemneuro.1c00492

Chand GB, Jiang H, Miller JP, Rhodes CH, Tu Z, Wong DF. Differential sphingosine-1-phosphate receptor-1 protein expression in the dorsolateral prefrontal cortex between schizophrenia type 1 and type 2. Front Psychiatry. 2022;13:827981.

pubmed: 35350429 pmcid: 8957823 doi: 10.3389/fpsyt.2022.827981

Liu H, Laforest R, Gu J, Luo Z, Jones LA, Gropler RJ, et al. Acute rodent tolerability, toxicity, and radiation dosimetry estimates of the S1P1-specific radioligand [(11)C]CS1P1. Mol Imaging Biol. 2020;22:285–92.

pubmed: 31165387 pmcid: 6893109 doi: 10.1007/s11307-019-01380-z

Luo Z, Gu J, Dennett RC, Gaehle GG, Perlmutter JS, Chen DL, et al. Automated production of a sphingosine-1 phosphate receptor 1 (S1P1) PET radiopharmaceutical [(11)C]CS1P1 for human use. Appl Radiat Isot. 2019;152:30–36.

pubmed: 31280104 pmcid: 6708718 doi: 10.1016/j.apradiso.2019.06.029

Brier MR, Hamdi M, Rajamanikam J, Zhao H, Mansor S, Jones LA, et al. Phase 1 evaluation of (11)C-CS1P1 to assess safety and dosimetry in human participants. J Nucl Med. 2022;63:1775–82.

pubmed: 35332093 pmcid: 9635683

Qiu L, Jiang H, Yu Y, Gu J, Wang J, Zhao H, et al. Radiosynthesis and evaluation of a fluorine-18 radiotracer [(18)F]FS1P1 for imaging sphingosine-1-phosphate receptor 1. Org Biomol Chem. 2022;20:1041–52.

pubmed: 35029272 pmcid: 8970350 doi: 10.1039/D1OB02225C

Liu H, Luo Z, Gu J, Jiang H, Joshi S, Shoghi KI, et al. In vivo characterization of four (18)F-labeled S1PR1 tracers for neuroinflammation. Mol Imaging Biol. 2020;22:1362–9.

pubmed: 32602083 pmcid: 7679043 doi: 10.1007/s11307-020-01514-8

Luo Z, Liu H, Yu Y, Gropler RJ, Klein RS, Tu Z. Synthesis and evaluation of highly selective quinazoline-2,4-dione ligands for sphingosine-1-phosphate receptor 2. RSC Med Chem. 2022;13:202–7.

pubmed: 35308025 pmcid: 8864552 doi: 10.1039/D1MD00357G

Luo Z, Rosenberg AJ, Liu H, Han J, Tu Z. Syntheses and in vitro evaluation of new S1PR1 compounds and initial evaluation of a lead F-18 radiotracer in rodents. Eur J Med Chem. 2018;150:796–808.

pubmed: 29604582 pmcid: 5908474 doi: 10.1016/j.ejmech.2018.03.035

Jiang H, Gu J, Zhao H, Joshi S, Perlmutter JS, Gropler RJ, et al. PET study of sphingosine-1-phosphate receptor 1 expression in response to S. aureus infection. Mol Imaging. 2021;2021:9982020.

pubmed: 34934406 pmcid: 8654346 doi: 10.1155/2021/9982020

Luo Z, Han J, Liu H, Rosenberg AJ, Chen DL, Gropler RJ, et al. Syntheses and in vitro biological evaluation of S1PR1 ligands and PET studies of four F-18 labeled radiotracers in the brain of nonhuman primates. Org Biomol Chem. 2018;16:9171–84.

pubmed: 30462126 pmcid: 6561338 doi: 10.1039/C8OB02609B

Qiu L, Jiang H, Zhou C, Wang J, Yu Y, Zhao H, et al. Discovery of a promising fluorine-18 positron emission tomography radiotracer for imaging sphingosine-1-phosphate receptor 1 in the brain. J Med Chem. 2023;66:4671–88.

pubmed: 36926861 pmcid: 11037415 doi: 10.1021/acs.jmedchem.2c01752

Ye M, Gai Y, Ji H, Jiang Y, Qiao P, Wang W, et al. A novel radioimmune (99m)Tc-labeled tracer for imaging sphingosine 1-phosphate receptor 1 in tumor xenografts: an in vitro and in vivo study. Front Immunol. 2021;12:660842.

pubmed: 34484174 pmcid: 8416251 doi: 10.3389/fimmu.2021.660842

Sehlin D, Syvanen S, Faculty M. Engineered antibodies: new possibilities for brain PET? Eur J Nucl Med Mol Imaging. 2019;46:2848–58.

pubmed: 31342134 pmcid: 6879437 doi: 10.1007/s00259-019-04426-0

PET imaging of neuroinflammation: any credible alternatives to TSPO yet?

Journal

Informations de publication

Résumé

Identifiants

Types de publication

Langues

Sous-ensembles de citation

Subventions

Informations de copyright

Références

Auteurs

Fabien Chauveau (F)

Alexandra Winkeler (A)

Sylvie Chalon (S)

Hervé Boutin (H)

Guillaume Becker (G)

Classifications MeSH